Description: Liver tolerance was first identified in the 1960s in the context of experimental liver transplantation. In many species, an allogeneic liver transplant will survive in an immune-competent recipient, without immunosuppression. This reveals an underlying bias towards immune tolerance to multiple liver antigens, including those encoded by transgenes (neo-self antigens), viruses and parasites. Many mechanisms have been proposed to explain liver tolerance, but there is no satisfactory model that unites them. The purpose of this project is to test two potential mechanisms and determine if they are mechanistically linked. Abundantevidence,includingsomegeneratedbyourlab,supportstheconceptthatfailureofCD8+T cellimmunityintheliverisduetolackofCD4+Tcellhelp,resultinginCD8+Tcelllossoffunction andclonalexhaustion.Otherevidence,includingPreliminaryDatawepresenthere,suggeststhat immunosuppressivemoleculesareinducedinlivercells,inparticularLiverSinusoidalEndothelial Cells,byInterferon?gamma.Ourcentralnovelideaisthatthesetwomechanismsoftoleranceare linked,andthePreliminaryDatastronglyimplicateLiverSinusoidalEndothelialcells.InSpecificAim 1wewilltestthehypothesisthatLiverSinusoidalEndothelialCellsarecentralincontrollingCD4+T cellactivationandtherebyimmunityversustolerance,whileinSpecificAim2wewilltestwhether Interferon?gammaregulatesthefunctionofLiverSinusoidalEndothelialCellstoinducetolerance.We haveoptimizedanAAV?basedmodeloflivertolerancetotesttheseconcepts,howeverthepossibility remainsopenthattheyareuniquetothemodel.ThereforeinSpecificAim3wetestthesameconcepts inamousemodelofHepatitisBinfection.Iftheconceptsholdinbothmodels,wearguethatthey revealagenerallyapplicablemechanismoftolerance. TherelationshipbetweenIFN?inducednegativefeedback,alsoknownasAdaptiveTolerance,and CD4+Tcellhelpmayholdinothertissues.Therefore,clarificationofthisrelationshipwillbeofbroad immunologicalinterest,andmayhavesignificanceinmodelsofinfection,immunityand immunopathologyinmanyorgansystems.